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Background The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period. Methods To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period. Results Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P Conclusions This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.

Background and objective: Klinefelter Syndrome (KS) is the most common sex chromosome aneuploidy (47, XXY) and cause of male hypergonadotropic hypogonadism. It is characterized by an extreme clinical heterogeneity in presentation, including infertility, hypogonadism, language delay, metabolic comorbidities, and neurocognitive and psychiatric disorders. Since testosterone is known to have organizational, neurotrophic and neuroprotective effects on brain, the condition of primary hypogonadism could play a role. Moreover, given that KS subjects have an additional X, genes on the extra-chromosome could also exert a significant impact. The aim of this narrative review is to analyze the available literature on the relationship between KS and neuropsychiatric disorders.Methods:To extend to the best of published literature on the topic, appropriate keywords and MeSH terms were identified and searched in Pubmed. Finally, references of original articles and reviews were examined.Results:Both morphological and functional studies focusing on the brain showed that there were important differences in brain structure of KS subjects. Different psychiatric disorders such as Schizophrenia, autism, attention deficit hyperactivity disorder, depression and anxiety were frequently reported in KS patients according to a broad spectrum of phenotypes. T supplementation (TRT) was not able to improve the psychotic disorders in KS men with or without overt hypogonadism.Conclusion:Although the risk of psychosis, depression and autism is increased in subjects with KS, no definitive evidence has been found in studies aiming at identifying the relationship between aneuploidy, T deficit and the risk of psychiatric and cognitive disorders in subjects affected by KS.

Purpose: The prevalence and the etiopathogenesis of thyroid dysfunctions in Klinefelter syndrome (KS) are still unclear. The primary aim of this study was to evaluate the pathogenetic role of hypogonadism in the thyroid disorders described in KS, with the scope to distinguish between patients with KS and hypogonadism due to other causes (Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, iatrogenic hypogonadism and acquired hypogonadotropic hypogonadism after surgical removal of pituitary adenomas) called non-KS. Therefore, we evaluated thyroid function in KS and in non-KS hypogonadal patients. Methods: This is a case–control multicentre study from KING group: Endocrinology clinics in university-affiliated medical centres. One hundred and seventy four KS, and sixty-two non-KS hypogonadal men were enrolled. The primary outcome was the prevalence of thyroid diseases in KS and in non-KS. Changes in hormonal parameters were evaluated. Exclusion criterion was secondary hypothyroidism. Analyses were performed using Student’s t test. Mann–Whitney test and Chi-square test. Results: FT4 was significantly lower in KS vs non-KS. KS and non-KS presented similar TSH and testosterone levels. Hashimoto’s thyroiditis (HT) was diagnosed in 7% of KS. Five KS developed hypothyroidism. The ratio FT3/FT4 was similar in both groups. TSH index was 1.9 in KS and 2.3 in non-KS. Adjustment for differences in age, sample size and concomitant disease in multivariate models did not alter the results. Conclusions: We demonstrated in KS no etiopathogenic link to hypogonadism or change in the set point of thyrotrophic control in the altered FT4 production. The prevalence of HT in KS was similar to normal male population, showing absence of increased risk of HT associated with the XXY karyotype.

Klinefelter syndrome (KS) is one of the most common genetic causes of male infertility. This condition is associated with much comorbidity and with a lower life expectancy. The aim of this review is to explore more in depth cardiovascular and metabolic disorders associated to KS. KS patients have an increased risk of cerebrovascular disease (standardized mortality ratio, SMR, 2.2; 95% confidence interval, CI, 1.6-3.0), but it is not clear whether the cause of the death is of thrombotic or hemorrhagic nature. Cardiovascular congenital anomalies (SMR, 7.3; 95% CI, 2.4-17.1) and the development of thrombosis or leg ulcers (SMR, 7.9; 95% CI, 2.9-17.2) are also more frequent in these subjects. Moreover, cardiovascular abnormalities may be at least partially reversed by testosterone replacement therapy (TRT). KS patients have also an increased probability of endocrine and/or metabolic disease, especially obesity, metabolic syndrome and type 2 diabetes mellitus. The effects of TRT on these abnormalities are not entirely clear. Purpose: The prevalence and the etiopathogenesis of thyroid dysfunctions in Klinefelter syndrome (KS) are still unclear. The primary aim of this study was to evaluate the pathogenetic role of hypogonadism in the thyroid disorders described in KS, with the scope to distinguish between patients with KS and hypogonadism due to other causes (Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, iatrogenic hypogonadism and acquired hypogonadotropic hypogonadism after surgical removal of pituitary adenomas) called non-KS. Therefore, we evaluated thyroid function in KS and in non-KS hypogonadal patients. Methods: This is a case–control multicentre study from KING group: Endocrinology clinics in university-affiliated medical centres. One hundred and seventy four KS, and sixty-two non-KS hypogonadal men were enrolled. The primary outcome was the prevalence of thyroid diseases in KS and in non-KS. Changes in hormonal parameters were evaluated. Exclusion criterion was secondary hypothyroidism. Analyses were performed using Student’s t test. Mann–Whitney test and Chi-square test. Results: FT4 was significantly lower in KS vs non-KS. KS and non-KS presented similar TSH and testosterone levels. Hashimoto’s thyroiditis (HT) was diagnosed in 7% of KS. Five KS developed hypothyroidism. The ratio FT3/FT4 was similar in both groups. TSH index was 1.9 in KS and 2.3 in non-KS. Adjustment for differences in age, sample size and concomitant disease in multivariate models did not alter the results. Conclusions: We demonstrated in KS no etiopathogenic link to hypogonadism or change in the set point of thyrotrophic control in the altered FT4 production. The prevalence of HT in KS was similar to normal male population, showing absence of increased risk of HT associated with the XXY karyotype.

Authors evaluated the effects of selective adrenergic blockade by means of doxazosin on blood pressure in 48 patients operated on for pheochromocytoma by a multicenter retrospective study. Age, tumor size, surgical approach, and operative time were analyzed as predictive factors of intraoperative hypertensive crises. Forty-eight patients underwent adrenalectomy—four open surgery and 44 laparoscopic surgery—for pheochromocytoma of adrenal glands from 1998 to 2008 after preoperative administration of doxazosin. Perioperative cardiovascular status modifications and surgical medium- and long-term outcomes were analyzed. There was no mortality, conversion rate was 4.5 per cent, and morbidity rate was 8.3 per cent. Intraoperative hypertensive crises (180/ 90 mmHg or higher) were observed in 14.5 per cent (seven of 48) of patients and were treated pharmacologically with no aftermath. None of the examined variables influenced the occurrence of intraoperative hypertensive episodes. Postoperative hypotension (lower than 90/60 mmHg) was observed in four of 48 patients (8.3%) and was treated by crystalloids and hydrocortisone. In the surgical treatment of pheochromocytoma, the preoperative adrenergic blockade by doxazosin does not prevent intraoperative hypertensive crises. Nevertheless, in our series, they were of short duration and were not associated with major cardiovascular complications. Perioperative hemodynamic instability was managed bypreoperative pharmacological treatment, allowing low morbidity.

A new family of angiogenic factors named endocrine-glandderived vascular endothelial growth factors (EG-VEGF)/prokineticins (PK) have been recently described as predominantly expressed in steroidogenic tissues. Whether the normal and malignant epithelial prostate cells and tissues express EG-VEGF/PK1 and PK2 and their receptors is still unknown. We studied the expression of EG-VEGF/PK1 and PK2and their receptors (PK-R1 and PK-R2) inhumanprostate and their involvement in cancer. Using immunohistochemistry, Western blot, and RT-PCR, we determined the expression of EG-VEGF/PK1 in normal prostate (NP) and malignant prostate tissues (PCa), in epithelial cell primary cultures from normal prostate (NPEC) and malignant prostate (CPEC) and in a panel of prostate cell lines. In NPEC, CPEC, and in EPN, a nontransformed human prostate epithelial cell line, EGVEGF/ PK1, PK2, PK-R1, and PK-R2 mRNA levels were evaluated by quantitative RT-PCR. EG-VEGF/PK1 transcript was found in PCa, in CPEC, in EPN, and in LNCaP, whereas it was detected at low level in NP and in NPEC. EG-VEGF/PK1 was absent in androgen-independent PC3 and DU-145 cell lines. Immunochemistry confirmed that EG-VEGF/PK1 protein expression was restricted to hyperplastic and malignant prostate tissues, localized in the glandular epithelial cells, and progressively increased with the prostate cancer Gleason score advancement. EG-VEGF/PK1 and PK2 were weakly expressed in NPEC and EPN. On the other hand, their transcripts were highly detected in CPEC. PK-R1 and PK-R2 were found in NPEC, EPN, and CPEC. Interestingly, CPEC showed a significantly (P < 0.05) higher expression of EG-VEGF/PK1, PK2, PK-R1, and PK-R2 compared with NPEC and EPN. We demonstrated that PKs and their receptors are expressed in human prostate and that their levels increased with prostate malignancy. It may imply that EG-VEGF/PK1 could be involved in prostate carcinogenesis, probably regulating angiogenesis. Thus, the level of EG-VEGF/PK1 could be useful for prostate cancer outcome evaluation and as a target for prostate cancer treatment in the future. (Endocrinology 147:4245-4251,2006)

Background Only few studies have assessed sexual dysfunction in men with Klinefelter syndrome (KS). Aim To define pooled prevalence estimates and correlates of erectile dysfunction (ED) and decreased libido (DL) in KS. Methods A thorough search of Medline, Embase and Web of Science was performed to identify suitable studies. Quality of the articles was scored using the Assessment Tool for Prevalence Studies. Data were combined using random effect models and the between-studies heterogeneity was assessed by the Cochrane’s Q and I2. The sources of heterogeneity were investigated by meta-regression and sub-group analyses. Funnel plot, Begg’s rank correlation and trim-and-fill test were used to assess publication bias. Main Outcome Measure The pooled prevalence of ED and DL in KS as well as 95% confidence intervals (CIs) were estimated from the proportion of cases of sexual dysfunction and the sample size. Variables that could affect the estimates were identified by linear meta-regression models. RESULTS Sixteen studies included collectively gave information about ED and DL in 482 and 368 KS men, respectively, resulting in a pooled prevalence of 28% (95% CI: 19%–36%) for ED and 51% (95% CI: 36%–66%) for DL, with a large heterogeneity. The trim-and-fill adjustment for publication bias produced a negligible effect on the pooled estimates. At the meta-regression analyses, a higher prevalence of ED was significantly associated with an older age but not with lower testosterone levels. In series with a mean age >35 years, the ED prevalence estimate increased up to 38% (95% CI: 31%–44%) with no heterogeneity (I2=0.0%, P=0.6). On the contrary, the prevalence of DL increased significantly as testosterone levels decreased, without a significant relationship with age. Clinical Implications While DL would largely reflect an androgen deficiency, in older men with KS, erectile function should be assessed irrespective of testosterone levels. Strength & Limitations This is the first meta-analysis defining pooled prevalence estimates and correlates of ED and DL in KS. Nevertheless, caution is required when interpreting results, due to the high risk of bias in many studies, as well as the dearth of data about psychosocial and/or psychosexological variables and age at the diagnosis. CONCLUSIONS ED and DL represent common clinical complaints in KS. While the prevalence of ED would increase with age, DL gets more common as serum testosterone decreases. Further studies are warranted to elucidate the pathogenetic mechanism(s) underlying the age-dependent increase in the prevalence of ED, apparently unrelated to the androgenic status.

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusiondependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX). We developed a multi-center follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95% Confidence Interval [CI]: 6.3–13.1). Multiple Cox regression analysis identified three key predictors: age showed a positive log-linear effect (adjusted hazard ratio [HR] for 50% increase 1.2, 95% CI: 1.1–1.3, P=0.005), the serum concentration of thyrotropin showed a positive linear effect (adjusted HR for 1 mIU/L increase 1.3, 95% CI: 1.1–1.4, P

Purpose: Low testosterone (T) in Klinefelter’s syndrome (KS) can contribute to typical features of the syndrome such as reduced bone mineral density, obesity, metabolic disturbances and increased cardiovascular risk. The aim of the present study is to review and meta-analyze all available information regarding possible differences in metabolic and bone homeostasis profile between T treated (TRT) or untreated KS and age-matched controls. Methods: We conducted a random effect meta-analysis considering all the available data from observational or randomized controlled studies comparing TRT-treated and untreated KS and age-matched controls. Data were derived from an extensive MEDLINE, Embase, and Cochrane search. Results: Out of 799 retrieved articles, 21 observational and 22 interventional studies were included in the study. Retrieved trials included 1144 KS subjects and 1284 healthy controls. Not-treated KS patients showed worse metabolic profiles (including higher fasting glycemia and HOMA index as well as reduced HDL-cholesterol and higher LDL-cholesterol) and body composition (higher body mass index and waist circumference) and reduced bone mineral density (BMD) when compared to age-matched controls. TRT in hypogonadal KS subjects was able to improve body composition and BMD at spinal levels but it was ineffective in ameliorating lipid and glycemic profile. Accordingly, TRT-treated KS subjects still present worse metabolic parameters when compared to age-matched controls. Conclusion: TRT outcomes observed in KS regarding BMD, body composition and glyco-metabolic control, are similar to those observed in male with hypogonadism not related to KS. Moreover, body composition and BMD are better in treated than untreated hypogonadal KS. Larger and longer randomized placebo-controlled trials are advisable to better confirm the present data, mainly derived from observational studies.

Objective: The association between chronic autoimmune thyroiditis (CAT) and differentiated thyroid cancer (DTC) remains controversial. The incidence of DTC increases when screening procedures are implemented, as typically occurs in CAT patients being routinely submitted to thyroid ultrasound (US). The aim of this study was to longitudinally evaluate the long-term development of DTC in patients with CAT. Design and methods: A retrospective longitudinal cohort study was designed. For the study, 510 patients with chronic autoimmune thyroiditis (CAT) with a 10-year follow-up were enrolled. Patients were divided in two groups according to the presence (CAT+ NOD+; n = 115) or absence (CAT+ NOD−; n = 395) of co-existent nodules at diagnosis. The main outcome measures were appearance of new thyroid-nodules and development of DTC during follow-up. Results: During a 10-year median follow-up period, new thyroid-nodules were detected in 34/115 (29.5%) patients in the CAT+ NOD+ group and in 41/395 (10.3%) in the CAT+ NOD− group (P Conclusions: In our series of CAT patients, the appearance of new thyroid-nodules was frequent, but none of them were found to be malignant. The presence of CAT appears to be associated with a negligible risk of developing clinically overt DTC.

Context Patients with adrenal insufficiency (AI) have excess mortality and morbidity, mainly due to cardiovascular (CV) diseases. The mechanisms for this is unclear. Objective To assess CV structure and function in AI patients on conventional replacement therapy and after switching to once-daily, modified-release hydrocortisone (OD-HC) in comparison with healthy matched controls. Methods This was a retrospective analysis of 17 adult AI patients (11 with primary AI, 6 with secondary AI) on stable replacement with cortisone acetate [median (minimum, maximum) 33.5 (12.5–50) mg] and, if needed, fludrocortisone [0.1 (0.05–0.2) mg], and 17 healthy matched controls. Ten patients were switched to an equivalent dose of OD-HC. Data from echocardiography, 24 h Holter-ECG and 24 h blood pressure monitoring were collected at baseline and 6 months after the switch to OD-HC. Results At baseline, AI patients had smaller left ventricular diastolic diameter (47.1 ± 4.2 vs. 51.6 ± 2.3 mm; P = 0.001) and left atrial diameter (34.9 ± 4.7 vs. 38.2 ± 2.6 cm; P = 0.018), and a higher ejection fraction (62.5 ± 6.9% vs. 56.0 ± 4.7%; P = 0.003) than controls. AI patients had lower nocturnal systolic and diastolic blood pressure than controls (108 ± 15 mmHg vs. 117 ± 8 mmHg; P = 0.038 and 65 ± 9 mmHg vs. 73 ± 7 mmHg; P = 0.008, respectively). After the switch to OD-HC, nocturnal diastolic blood pressure normalised. No significant changes were observed in echocardiographic and Holter-ECG parameters following the switch. Conclusions AI patients on conventional treatment display cardiovascular abnormalities that could be related to hypovolemia. Switch to OD-HC seems to have beneficial effect on blood pressure profile, but no effect on cardiovascular structure and function.

Purpose: The aim of this study was to evaluate the somatotroph axis in a large series of patients with prolactinoma to verify the prevalence of silent acromegaly in this population. Methods: A hundred and forty-four patients were enrolled in a multicenter study: 90 were already on cabergoline (CAB) and enrolled in a cross-sectional arm (group A) with random PRL, GH and IGF-I determination on treatment (≥3months), whereas 54 untreated patients were enrolled at diagnosis in a prospective arm (group B) with PRL, GH and IGF-I measurement before and after 6 and 12months of treatment. In the presence of high IGF-I, CAB was withdrawn for 3months and GH, IGF-I, PRL and GH during an oral Glucose Tolerance Test (OGTT) were obtained. Results: High IGF-I levels (ULN 1.01–1.56) were observed in 9 patients (6.25%, 5F). After CAB withdrawal, IGF-I levels normalized in 5/9 patients, GH was&nbsp

Purpose: Serum-negative-chronic-autoimmune-thyroiditis (SN-CAT) is considered a milder variant of classic Hashimoto’s thyroiditis (CHT). However, its prevalence remains unknown and it is still unclear whether SN-CAT behaves differently in terms of l-thyroxine (LT4) substitution treatment of hypothyroidism. Aims of this study were to estimate the prevalence of SN-CAT in a large series of hypothyroid patients and to compare LT4 requirements in hypothyroid patients with SN-CAT and CHT. Methods: Five-hundred-eighty-one consecutive patients with primary-autoimmune-hypothyroidism were enrolled in a cross-sectional study. LT4 requirements and thyroid-volume changes were longitudinally evaluated in 49 hypothyroid patients with SN-CAT and in 98 sex and age-matched hypothyroid patients with CHT. Results: In our series the prevalence of SN-CAT was 20.8%. At diagnosis, patients in the CHT and SN-CAT groups had similar male/female ratio, age and BMI, while serum TSH and thyroid-volume were significantly greater in the CHT group. In the longitudinal study, during a follow-up of 8.9 ± 4.6years, 8 out of 49 (16.3%) SN-CAT patients developed positive tests for of circulating TPO-Ab and/or Tg-Ab. Thyroid-volume significantly decreased in CHT patients, but not in those with SN-CAT. The maximum daily substitution dose of LT4 was smaller in SN-CAT patients as compared with the CHT ones. Multivariate analysis showed that age, BMI, basal TSH and thyroid antibody status independently and significantly predicted the maximum daily substitution dose of LT4. Conclusions: SN-CAT accounts for a significant proportion of patients with autoimmune hypothyroidism. Compared with hypothyroid patients diagnosed with CHT, the SN-CAT ones require smaller doses of LT4 to correct their hypothyroidism.

Objective The purpose of this prospective study was to assess the effects of selenium supplementation on TSH and interferon-γ inducible chemokines (CXCL9, CXCL10 and CXCL11) levels in patients with subclinical hypothyroidism due to Hashimoto's thyroiditis. Patients and methods Patients with subclinical hypothyroidism due to Hashimoto thyroiditis were prospectively enrolled in the SETI study. They received 83 mcg of selenomethionine/day orally in a soft gel capsule for 4 months with water after a meal. No further treatment was given. All patients were measured thyroid hormone, TPOAb, CXCL9, CXCL10, CXCL11, iodine, and selenium levels at baseline and at study end. Results 50 patients (43/7 female/male, median age 43.9 ± 11.8 years) were enrolled, of which five withdrew from the study. At the end of the study, euthyroidism was restored in 22/45 (48.9%) participants (responders), while 23 patients remained hypothyroid (non-responders). There were no significant changes in TPOAb, CXCL9, CXCL10, CXCL11, and iodine levels from baseline to the end of the study in both responders and non-responders. TSH levels were re-tested six months after selenomethionine withdrawal: 83.3% of responding patients remained euthyroid, while only 14.2% of non-responders became euthyroid. Conclusions The SETI study shows that short-course supplementation with selenomethionine is associated to a normalization of serum TSH levels which is maintained 6 months after selenium withdrawal in 50% of patients with subclinical hypothyroidism due to chronic autoimmune thyroiditis. This TSH-lowering effect of selenium supplementation is unlikely to be related to changes in humoral markers of autoimmunity and/or circulating CXCL9.

Background Laparoscopic adrenalectomy is considered the gold standard technique for the treatment of benign small and medium size adrenal masses (

Background: The real efficacy of selenium supplementation in Hashimoto’s thyroiditis (HT) is still an unresolved issue. Objectives: We studied the short-term effect of l-selenomethionine on the thyroid function in euthyroid patients with HT. Our primary outcome measures were TSH, thyroid hormones, thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TGAb) levels and thyroid echogenicity after 6months of l-selenomethionine treatment. The secondary outcome measure was serum CXCL10 levels. Methods: In a placebo-controlled randomized prospective study, we have enrolled untreated euthyroid patients with HT. Seventy-six patients were randomly assigned to receive l-selenomethionine 166µg/die (SE n=38) or placebo (controls n=38) for 6months. TSH, free T 4 (FT 4 ), free T 3 (FT 3 ), TPOAb and CXCL10 serum levels were assayed at time 0, after 3 and 6months. An ultrasound examination of the left and right thyroid lobe in transverse and longitudinal sections was performed. A rectangular region, the region of interest, was selected for analysis. Results: TSH, FT4, FT3, TPOAb, thyroid echogenicity and CXCL10 were not statistically different between SE and control groups at time 0, after 3 and 6months. In the SE group, FT 4 levels were significantly decreased (P&nbsp

BACKGROUND: Hemostasis during thyroidectomy is essential; however, the safest, most efficient, and most cost-effective way to achieve this is unclear. This randomized, multicenter, single-blind, prospective study evaluated the efficacy and safety of using different hemostatic approaches in patients undergoing total thyroidectomy. METHODS: Patients aged ≥18 to 70 years were randomized to Floseal + a harmonic scalpel (HS), Floseal alone, HS alone, or standard total thyroidectomy. Primary endpoint was 24-hour drain output. Secondary endpoints included surgery duration and complications. RESULTS: Two hundred and six patients were randomized to Floseal + HS (n = 52), Floseal alone (n = 54), HS alone (n = 50), and standard total thyroidectomy (n = 50). The 24-hour drain output was lower in the Floseal + HS group compared with standard thyroidectomy. Floseal + HS also had a shorter surgery time (P < .0001) versus the other 3 treatments. CONCLUSION: Floseal + HS can be effective at reducing postsurgical drain output and provides a complementary hemostatic approach in patients undergoing total thyroidectomy. © The Author(s) 2015. Background. Hemostasis during thyroidectomy is essential; however, the safest, most efficient, and most cost-effective way to achieve this is unclear. This randomized, multicenter, single-blind, prospective study evaluated the efficacy and safety of using different hemostatic approaches in patients undergoing total thyroidectomy. Methods. Patients aged ≥18 to 70 years were randomized to Floseal + a harmonic scalpel (HS), Floseal alone, HS alone, or standard total thyroidectomy. Primary endpoint was 24-hour drain output. Secondary endpoints included surgery duration and complications. Results. Two hundred and six patients were randomized to Floseal + HS (n = 52), Floseal alone (n = 54), HS alone (n = 50), and standard total thyroidectomy (n = 50). The 24-hour drain output was lower in the Floseal + HS group compared with standard thyroidectomy. Floseal + HS also had a shorter surgery time (P

Patients with Klinefelter syndrome (KS) exhibit an increased cardiovascular risk, but underlying mechanisms are largely unknown. The present cross-sectional study has been conducted to evaluate platelet reactivity and the expression of platelet activation markers (8-iso-prostaglandin F2α[8-iso-PGF2α] and 11-dehydro-thromboxane-B₂[11-dehydro-TXB2]) in KS patients and healthy controls. Twenty-three consecutive KS patients under testosterone replacement therapy have been included as case group and 46 age-matched healthy males recruited among hospital staff served as controls. Light transmission aggregometry was performed in both cases and controls and maximal platelet aggregation (max-A%) was defined as maximal light transmittance reached within 5min after the addition of 0.2 or 0.4mm arachidonic acid (AA). A≥50% irreversible light transmittance (LT-50%) following platelet stimulation defined an adequate platelet aggregation and AC-50% was defined as the minimal agonist concentration needed to achieve LT-50%. The AC-50% was 0.26mm AA for KS and 0.36mm for controls (p&nbsp

Multiple endocrine neoplasia 2A (MEN 2A) is an inherited dominant syndrome characterised by medullary thyroid carcinoma, adrenal pheochromocytoma and hyperparathyroidism due to specific RET proto-oncogene mutations. Fertile MEN 2A women are at risk of complicated pregnancy because of unrecognised pheochromocytoma and transmission of RET mutation to the progeny. This condition may cause psychological distress in affected pregnant patients and their families. Here we describe the genetic prenatal testing, the pregnancy management and obstetric outcome in a MEN 2A patient with a right side adrenal hyperplasia and elevated calcitonin levels, a condition suspicious for possible recurrence of pheochromocytoma. We confirm that maternal or fetal complications are rare when MEN 2A diagnosis is made before pregnancy and an accurate monitoring is instituted. Furthermore, our results indicate that prenatal testing for RET mutations is highly recommended in making decisions and assuring parents on the lifelong risk of tumors. This will avoid the psychological distress that can further complicate the pregnancy of affected women.

An increased secretion of cytokines and growth factors has been hypothesised to play a role in the abnormal growth of keloid fibroblasts. The aim of this study was to evaluate the effect of the calcium antagonist verapamil on the interleukin-6 (IL-6) and vascular endothetial growth factor (VEGF) secretion, as well as on cellular growth, in primary cultures of fibroblasts derived from the central part of keloid lesions. These cells grew faster than peripheral keloid and nonkeloid fibroblasts, and, in long-term cultures, became stratified assuming a three-dimensional structure. Compared with peripheral and nonkeloid fibroblasts, central keloid fibroblasts presented an increased production of both IL-6 and VEGF (P

In this study, we evaluated by reverse transcription-polymerase chain reaction (RT-PCR) the expression pattern of retinoic acid receptors (RAR) alpha, beta, and gamma and cellular retinoic acid binding protein-I (CRBP-I) genes in 12 primary cultures of fibroblasts (F) from orbital tissue of Graves' ophthalmopathy (GO) patients. We also studied the in vitro effects of all-trans retinoic acid (RA) and N-(4-hydroxyphenil)-retinamide (4HPR), a less toxic and better tolerated synthetic derivative of RA, on cell morphology, growth, apoptosis, and cyclic adenosine monophosphate (cAMP) accumulation. All primary cultures expressed RAR alpha, beta, gamma, and CRBP-I. FGO treated with RA and 4HPR (10(-7) mol/L) presented morphologic changes and significantly inhibited cell growth after 72 hours. At 96 hours of drug exposure, apoptosis was detected in 15% and 50% of RA- and 4HPR (10(-7) mol/L)-treated cells, and p53 protein increased in cell lysates. 4HPR induced a 70% decrease of Bcl-2 protein. After 30 minutes of RA and 4HPR (10(-7) mol/L) exposure, a 20% decrease of basal cAMP accumulation was seen, and forskolin cAMP-induced increase was abolished. The expression of RAR alpha, beta, gamma, and CRBP-I in primary cultures of FGO indicates that they are targets for retinoids. Moreover, we show that RA and 4HPR are able to induce morphologic changes, inhibition of cell growth, and apoptosis in FGO exerting their effects through RAR-modulated pathways. The rapid inhibition of cAMP accumulation indicates that a novel nonclassic retinoid pathway may also be involved. Finally, the potent in vitro effects of 4HPR, a retinoid derivative with fewer adverse reactions in vivo, could justify further investigations on a clinical application of retinoids in GO.

Chordoma of thoracic vertebras is a very rare locally invasive neoplasm with low grade malignancy arising from embryonic notochordal remnants. Radical surgery remains the cornerstone of the treatment. We describe a case of multifocal T1-T2 chordoma, without bone and disc involvement, incidentally misdiagnosed as a paraganglioma, occurring in a 47-year-old male asymptomatic patient. Neoplasm was radically removed by an endocrine surgeon through a right extended cervicotomy. A preoperative reliable diagnosis of chordoma, as in the reported case, is often difficult. Radical surgery can provide a favorable outcome but, given the high rates of local recurrence of this neoplasm, a strict and careful follow-up is recommended. Although very rare, chordoma should be suggested in the differential diagnosis of the paravertebral cervical masses of unknown origin. Spine surgeon consultation and a FNB should be routinely included in the multidisciplinary preoperative work-up of these neoplasms.

Total thyroidectomy (TT) is the standard of care for differentiated thyroid cancer (DTC), but still there is no consensus about the role of routine use of prophylactic central lymph node dissection. The aim of this study was to analyze our results of TT without prophylactic central lymphadenectomy in the treatment of DTC. Clinical records, between January 1998 and December 2005, of 221 patients undergoing TT, without prophylactic central lymph node dissection, were retrospectively evaluated. Two hundred and eleven patients (95.47 %) also underwent radioiodine (RAI) ablation followed by thyroid stimulating hormone (TSH) suppression therapy. In patients with loco-regional lymph nodal recurrence, lateral and central lymph node dissection was performed. The incidence of permanent hypoparathyroidism (iPTH

Background Minimally invasive adrenalectomy for pheochromocytoma (PCC) is a complex surgical procedure especially because of the haemodynamic instability due to the excessive secretion of cathecolamines, which may result in a considerable risk of conversion and complications. Aim By a multicentric retrospective study, the authors reported the results of laparoscopic adrenalectomies in patients operated for adrenal pheochromocytomas with the aim of investigating the role of the laparoscopic approach in managing adrenal disease. Methods Sixty patients, preoperatively treated with a selective alpha1-blocker, underwent 61 laparoscopic adrenalectomies for PCC smaller or larger than 6 cm – group A (≤6 cm), group B (>6 cm). We compared the two groups of patients analyzing haemodynamic instability, operative time, conversion rate, incidence of complications, length of hospital stay and medium and long-term outcomes. Results In 23 cases tumor was >6 cm in diameter. Average operative time was 165 min, with a 5% conversion rate. There was no mortality and morbidity rate was 8.3%. Intraoperative hypertensive crises were registered in 15% of patients, whereas 5/60 patients had hypotensive crises. After comparing the two groups of patients, no statistically significant differences in terms of haemodynamic instability, operative time, conversion rate, morbidity and length of hospital stay were observed. Conclusions As a surgical treatment of pheochromocytomas, laparoscopic adrenalectomy is an effective and safe approach, in selected cases even for PCCs >6 cm in diameter, although patients with such large tumors may have a higher conversion rate and more intraoperative hypertensive crises. Preoperative selective adrenergic blockade does not prevent intraoperative hypertensive crises, but by facilitating the pharmacological management of the perioperative haemodynamic instability, may avoid the onset of major adverse cardiovascular complications.

Lymph node metastases are responsible for shorter survival in oral squamous cell carcinoma (OSCC). The aim of the present study was to assess the node metastasis frequency and survival according to the node metastasis features in 121 neck dissections (NDs) performed for OSCC, identifying evidence-based correlations and contrasts with previous literature. The retrospective study involved 121 patients affected by OSCC who had undergone modified radical ND (MRND) for therapeutic, elective reasons or after intraoperative positivity to metastasis of sentinel lymph nodes (SLN+). Node metastasis frequency and behaviour (typical vs. atypical) and their number and distribution according to pre-surgical cTNM cancer staging were considered and overall survival Kaplan-Meier curves were calculated for each group in order to compare mortality according to ND type (elective, therapeutic, after SLN+), lymph node metastatic pattern (typical or atypical), size (micrometastasis vs. macrometastasis) and number. Results showed statistically significant different overall survival according to pre-surgical staging, number of lymph nodes harvested and intent to surgery. Sentinel lymph node resulted in the sole positive node affected by metastasis in small cT1- cT2/cN0 OSCC and an ND subsequent to its positivity during intraoperative assessment may be considered an overtreatment.

ContextCDKN1B encodes the cyclin-dependent kinase inhibitor p27Kip1 and is mutated in multiple endocrine neoplasia-like syndromes. CDKN1B also harbors single nucleotide polymorphisms; the T/G transversion at nucleotide 326 (the V109G variant) has been reported to be protective in breast, hereditary prostate, and pancreatic tumors. Association of CDNK1B mutations or polymorphisms with sporadic medullary thyroid carcinoma (MTC) has not been investigated yet.Objective and designWe screened germline DNA from 84 patients affected by sporadic MTC and 90 healthy age- and gender-matched controls for CDKN1B mutations or polymorphisms by PCR amplification and sequencing of the amplicons. We also tested all germline and 50 tumor tissue DNA for RET proto-oncogene mutations. Computed tomography, ultrasound scans, and serum calcitonin were carried out before surgery and during the follow-up and associated with CDKN1B polymorphism and disease remission.ResultsThe T/G transversion at nucleotide 326 was the only DNA variation detected. The overall frequency of the T/G and G/G alleles in combination was 46.4%. This variant (V109G) was correlated with post-operative calcitonin levels in the normal range and biochemical remission. Conversely, the wild-type (T/T) allele was associated with post-operative calcitonin levels above normal and a higher risk to develop clinical recurrence and distant metastases. Somatic RET mutations were significantly associated with a more aggressive behavior especially in wild-type allele-bearing patients.ConclusionsCollectively, in sporadic MTC, the CDKN1B V109G polymorphism correlates with a more favorable disease progression than the wild-type allele and might be considered a new promising prognostic marker.

"Abstract. Transcriptional silencing by CpG island hypermethylation plays a critical role in endometrial carcinogenesis. In a collection of benign, premalignant and malignant endometrial lesions, a methylation profile of a complete gene panel, such steroid receptors (ERα, PR), DNA mismatch repair (hMLH1), tumor-suppressor genes (CDKN2A\/P16 and CDH1\/E-CADHERIN) and WNT pathway inhibitors (SFRP1, SFRP2, SFRP4, SFRP5) was investigated in order to demonstrate their pathogenetic role in endometrial lesions. Our results indicate that gene hypermethylation may be an early event in endometrial endometrioid tumorigenesis. Particularly, ERα, PR, hMLH1, CDKN2A\/P16, SFRP1, SFRP2 and SFRP5 revealed a promoter methylation status in endometrioid carcinoma, whereas SFRP4 showed demethylation in cancer. P53 immunostaining showed weak-focal protein expression level both in hyperplasic lesions and in endometrioid cancer. Non-endometrioid cancers showed very low levels of epigenetic methylations, but strong P53 protein positivity. Fisher exact test revealed a statistically significant association between hMLH1, CDKN2A\/P16 and SFRP1 genes methylation and endometrioid carcinomas and between hMLH1 gene methylation and peritumoral endometrium (p < 0.05). Our data confirm that the methylation profile of the peritumoral endometrium is different from the altered molecular background of benign endometrial polyps and hyperplasias. Therefore, our findings suggest that the methylation of hMLH1, CDKN2A\/P16 and SFRP1 may clearly distinguish between benign and malignant lesions. Finally, this study assessed that the use of an epigenetic fingerprint may improve the current diagnostic tools for a better clinical management of endometrial lesions."

The nuclear protein methyl-transferase Retinoblastoma-interacting zinc-finger protein 1 (RIZ1) is considered to be a downstream effector of estrogen action in target tissues. Silencing of RIZ1 expression is common in many tumors. We analyzed RIZ1 expression in normal and malignant prostate tissue and evaluated whether estradiol (E2) or dihydrotestosterone (DHT) treatment modulated RIZ1 in cultured prostate epithelial cells (PEC). Moreover, we studied the possible involvement of RIZ1 in estrogen action on the EPN prostate cell line, constitutively expressing both estrogen receptor (ER)-alpha and beta. RIZ1 protein, found in the nucleus of normal PECs by immunohistochemistry, was progressively lost in cancer tissues as the Gleason score increased and was only detected in the cytoplasmic compartment. RIZ1 transcript levels, as assayed by semi-quantitative RT-PCR in primary PEC cultures, were significantly reduced in cancer cells (P < 0.05). In EPN DHT treatment significantly increased RIZ1 transcript and protein levels (P < 0.05); E2 induced a reduction of S phase without significant changes of RIZ1 expression. In E2-treated EPN cell extracts RIZ co-immunoprecipitated with ERbeta and ERalpha. Our data demonstrate that RIZ1 is expressed in normal PECs and down-regulated in cancer cells, with a switch of its sub-cellular localization from the nucleus to the cytoplasm upon cancer grade progression. RIZ1 expression levels in the PECs were modulated by DHT or E2 treatment in vitro. Furthermore, the E2 effects on ER-expressing prostate cells involve RIZ1, which confirms a possible role for ER-mediated pathways in a non-classic E(2)-target tissue.

Expansion of adipose tissue in the orbits is a key feature of Graves' ophthalmopathy. Recent evidence shows that orbital fibroblasts are committed to differentiate into adipocytes under appropriate stimuli. Rosiglitazone, an agonist of the nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPARgamma) is able to induce both differentiation of orbital fibroblasts into mature adipocytes and expression of the TSH receptor (TSHr) gene. Several studies have suggested an important role of the high mobility group AT-hook 2 (HMGA2) gene in adipocytic cell growth and development. To investigate further the association between adipogenesis-related genes and orbital fibroblasts, we treated fibroblasts from Graves' ophthalmopathy (FGOs) and from normal orbital tissues with fenofibrate, a specific agonist for PPARalpha. We then evaluated the expression of the PPARalpha, PPARgamma2, HMGA2, leptin and TSHr genes before and after 24 h of fenofibrate treatment, using semiquantitative and real-time PCR. For up to 96 h after exposure to fenofibrate, FGOs differentiated into adipocytes. PPARalpha and PPARgamma2 were expressed more in FGOs than in normal cultures, whereas TSHr mRNA was detected only in FGOs. Expression of HMGA2 mRNA and protein was significantly increased in FGOs from 6 to 24 h after fenofibrate, confirming its role in the early phase of adipocyte differentiation. Treatment with fenofibrate for 24 h significantly increased the expression of leptin and TSHr genes. Moreover, TSH treatment significantly increased the accumulation of cAMP, demonstrating that FGOs express functional TSHr. The high level of expression of PPARalpha other than PPARgamma2 transcripts and the stimulating effect of fenofibrate on adipogenesis and on HMGA2, leptin and TSHr genes also indicate that the PPARalpha pathway plays an important part in the adipocyte differentiation of FGOs. These findings suggest that novel drugs to antagonize PPARalpha, other than the PPARgamma signalling system, may also need to be considered in the treatment or prevention of Graves' ophthalmopathy.

The radiolabeled somatostatin (SST) analog octreotide accumulates within the orbits of active Graves’ ophthalmopathy (GO), and octreotide and lanreotide have been proposed to treat this disorder. It is still unclear which retroorbital cells the SST analogs target. Lymphocytic infiltration of retroorbital tissues is a peculiarity of GO, and labeled octreotide could accumulate at specific sites on retroorbital-activated lymphocytes. The accumulation of radiolabeled analogs is due to the interaction with specific cell surface SST receptors. Five subtypes of somatostatin receptors (SST1–5), member of the G protein-coupled, seven-transmembrane superfamily, are described. It still unknown which SST subtype is expressed in retroorbital activated lymphocytes. The aim of this study was to evaluate the expression of SST1–5 genes in lymphocytes recovered from retroorbital tissues obtained from patients with GO undergoing orbital decompression. Cultured phytohemagglutinin-stimulated lymphocytes from retroorbital blood samples, drawn during orbital surgery in five patients with GO and in two control patients without autoimmune or thyroid diseases and without orbital inflammatory conditions, were also studied. RT-PCR of total RNA extracted from lymphocytes was performed using primers for SST1–5 and, as internal control, for glyceraldehyde-3-phosphate dehydrogenase. All SSTs transcripts were found in lymphocytes both from GO retroorbital tissues and blood samples. The levels of expression of SST1, -2, and -4 mRNA were higher than those of the SST3 and -5 transcripts. In the lymphocytes from control subjects, the SST subtypes with high affinity for octreotide were barely found. The presence, even if at different concentrations, of all SST1–5 receptors in retroorbital lymphocytes from GO shows that they are targeted by SST analogs and could explain the effects described in GO patients treated with SST analogs. (J Clin Endocrinol Metab 87: 5125–5129, 2002)

Retinoids seem to act as agents of chemoprevention and differentiation in breast diseases. Their action is mediated by nuclear receptors, retinoic acid receptors (RAR alpha, RAR beta, RAR gamma) and retinoid X receptors (RXR alpha, RXR beta, RXR gamma) and modulated by cellular retinol binding proteins (CRBP). There are few published data on CRBP expression. In this study, we evaluated the expression of RAR alpha, beta and gamma and CRBP type I (CRBP-I) gene expression in fibrocystic disease (FD) and in breast cancer (BC), studying 14 FD and 20 BC surgical samples by reverse transcription (RT)-PCR. We also evaluated mRNA concentrations in cancer samples by a semiquantitative PCR method, co-amplifying RAR alpha, RAR beta and CRBP-I genes with an unrelated gene, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), as internal control. All benign and malignant breat tissues expressed RAR alpha, beta and gamma, and CRBP-I mRNAs. A greater concentration of RAR beta mRNA was detected in cancer tissues with lower oestrogen and progesterone receptor concentrations, whereas RAR alpha was detected in variable concentrations that were not related to those of steroid receptors. The CRBP-I concentration was similar in all samples studied. We demonstrated that all three RARs and CRBP-I transcripts are expressed in FD, and that RAR beta, RAR gamma and CRBP-I mRNAs also are present in BC tissues. This indicates that both malignant and benign breast tissues may be target for retinoids, justifying the use of natural and synthetic vitamin A derivatives in the chemoprevention of breast disease.

To explore the mechanism underlying the effects of the somatostatin (SST) analogue octreotide in Graves' ophthalmopathy (GO), we investigated the expression of SST and of SST receptor (sst(1-5)) genes in primary cultures of fibroblasts established from retroorbital tissue of GO patients and of control subjects. We determined also SST specific binding sites by competitive binding of [(125)ITyr(11)]SST-14 and the effect of octreotide on cell growth, cAMP accumulation, Bcl-2 intracellular levels and apoptosis in GO fibroblast primary cultures. All primary cultures expressed the SST gene transcript and one or more ssts that have a high affinity for the two analogues (class 1 sst. The sst(2) transcript was found in nine, sst(3) in five and sst(5) in eight out of ten GO cell cultures. Sst(2) was detected in all six, and sst(3) in four out of the six control cell cultures. Sst(4) was absent from all samples, and sst(1) was found only in six out of the ten GO samples. SST-14 and octreotide inhibited the binding of [(125)I-Tyr(11)]SST-14 with a half-maximal inhibition of binding (IC(50)) of 0.80+/-0.37 and 33. 7+/- 33.1 nmol/l respectively in GO cell cultures, and with an IC(50) of 0.9 and 1.5 nmol/l in control cultures. Octreotide (10(-6) and 10(-7) M) significantly decreased (P